1. Field of the Invention
This invention relates to novel compounds useful as cardiovascular agents, to novel pharmaceutical compositions and to a novel method of treating cardiovascular disorders.
2. Description of the Prior Art
Endothelium-derived relaxing factor (EDRF) is a labile humoral agent which is part of a cascade of interacting agents involved in the relaxation of vascular smooth muscle. EDRF is thus important in the control of vascular resistance to blood flow and in the control of blood pressure. Some vasodilators act by causing EDRF to be released from endothelial cells. (See Furchgott, Ann. Rev. Pharmacol.Toxicol. 24, 175-197, 1984.) In 1987, Palmer et al., presented evidence that EDRF is identical to the simple molecule, nitric oxide, NO (Nature 317, 524-526, 1987), though more recently, that conclusion has been challenged (Myers et al., Nature, 345, 161-163, 1990). It has been hypothesized for years that many nitrovasodilators, which mimic the effect of EDRF, like glyceryl trinitrate, amyl nitrite, NaNO.sub.2 and sodium nitroprusside (SNP), do so by virtue of their conversion to a common moiety, namely NO, which is also a vasodilator. (See Kruszyna et al., Tox. & Appl. Pharmacol., 91, 429-438, 1987; Ignarro, FASEB J. 3, 31-36, 1989; and Ignarro et al., J. Pharmacol. Exper. Therapeutics 218(3), 739-749, 1981.)
Numerous nitric oxide-nucleophile complexes have been described, e.g., Drago, ACS Adv. Chem. Ser., Vol. 36, p. 143-149 (1962). See also R. Longhi and R. S. Drago, Inorg. Chem. 2 85, (1963). Some of these complexes are known to evolve nitric oxide on heating or hydrolysis, e.g., Hansen, et al., IARC SCI. PUBL., Vol. 41, p. 21-29 (1982).
Evidence that nitric oxide is released from the endothelial cells and is responsible for the relaxation of the vascular smooth muscle, and hence the control of blood pressure, has resulted in the development of artificial agents that can deliver nitric oxide in vivo. A very important class of such agents is the nitric oxide-nucleophile complexes. Recently, a method for treating cardiovascular disorders in a mammal with certain nitric oxide-nucleophile complexes has been disclosed in U.S. Pat. No. 4,954,526.
The cardiovascular agents described in U.S. Pat. No. 4,954,526 are complexes formed from nitric oxide and primary amines, and esters, ethers or other derivatives of the resulting adducts. These compounds spontaneously release nitric oxide in vivo, and it is this release which accounts for their biological activity. While these nitric oxide-nucleophile complexes have been found to exhibit biological activity through their release of nitric oxide, novel derivatives of these nitric oxide-nucleophile complexes which also release nitric oxide and which exhibit improved potency and/or stability would also be beneficial.
Thus, it is a principal object of the present invention to provide novel cardiovascular agents useful in treating cardiovascular disorders.
It is another object of the invention to provide novel cardiovascular agents with improved potency.
It is further object of the invention to provide novel cardiovascular agents with improved stability.
It is yet another object to provide pharmaceutical compositions suitable for use in the treatment of cardiovascular disorders.
It is also an object of the invention to provide a method for the treatment of cardiovascular disorders.
These and other objects and advantages will be apparent from the following description of the invention.